22-37479385-C-G

Variant names:

• chr22-37479385-C-G
• rs1165562615
• NM_002405.4:c.521G>C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_002405.4(MFNG):​c.521G>C​(p.Arg174Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000688 in 1,452,820 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R174Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: MFNG NM_002405.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.86
• Publications: 0 publications found

Genes affected

MFNG (HGNC:7038): (MFNG O-fucosylpeptide 3-beta-N-acetylglucosaminyltransferase) This gene is a member of the glycosyltransferase 31 gene family. Members of this gene family, which also includes the LFNG (GeneID: 3955) and RFNG (GeneID: 5986) genes, encode evolutionarily conserved glycosyltransferases that act in the Notch signaling pathway to define boundaries during embryonic development. While their genomic structure is distinct from other glycosyltransferases, these proteins have a fucose-specific beta-1,3-N-acetylglucosaminyltransferase activity that leads to elongation of O-linked fucose residues on Notch, which alters Notch signaling. The protein encoded by this gene may control Notch signaling in claudin-low breast cancer. [provided by RefSeq, May 2018]

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.747

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002405.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MFNG	NM_002405.4	MANE Select	c.521G>C	p.Arg174Pro	missense	Exon 4 of 8	NP_002396.2
	MFNG	NM_001166343.2		c.479G>C	p.Arg160Pro	missense	Exon 3 of 7	NP_001159815.1	O00587-2
	MFNG	NR_029413.2		n.679G>C		non_coding_transcript_exon	Exon 3 of 7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MFNG	ENST00000356998.8	TSL:1 MANE Select	c.521G>C	p.Arg174Pro	missense	Exon 4 of 8	ENSP00000349490.3	O00587-1
	MFNG	ENST00000968703.1		c.521G>C	p.Arg174Pro	missense	Exon 4 of 9	ENSP00000638762.1
	MFNG	ENST00000968704.1		c.521G>C	p.Arg174Pro	missense	Exon 4 of 8	ENSP00000638763.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.88e-7 AC: 1 AN: 1452820 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 722468

African (AFR) AF: 0.00 AC: 0 AN: 32902

American (AMR) AF: 0.00 AC: 0 AN: 43228

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25850

East Asian (EAS) AF: 0.00 AC: 0 AN: 38866

South Asian (SAS) AF: 0.0000117 AC: 1 AN: 85220

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53338

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5722

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1107654

Other (OTH) AF: 0.00 AC: 0 AN: 60040

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.82
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.21
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.72	D
Eigen	Pathogenic	0.68
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.87	D
M_CAP	Uncertain	0.15	D
MetaRNN	Pathogenic	0.75	D
MetaSVM	Uncertain	0.073	D
MutationAssessor	Uncertain	2.6	M
PhyloP100		2.9
PrimateAI	Uncertain	0.52	T
PROVEAN	Pathogenic	-4.8	D
REVEL	Uncertain	0.58
Sift	Uncertain	0.0080	D
Sift4G	Uncertain	0.030	D
Polyphen		0.99	D
Vest4		0.93
MutPred		0.66		Gain of glycosylation at R174 (P = 0.0232)
MVP		0.56
MPC		0.93
ClinPred		0.96	D
GERP RS		5.2
Varity_R		0.72
gMVP		0.86
Mutation Taster		=47/53	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1165562615; hg19: chr22-37875423;